Development of a core outcome set for venous leg ulceration (CoreVen) research evaluations (protocol)

BackgroundA venous leg ulcer is a chronic leg wound caused by poor venous blood circulation in the lower limbs. It is a recurring condition causing pain, malodour, reduced mobility, and depression. Randomised controlled trials evaluating treatments for venous leg ulcers provide important evidence to inform clinical decision-making. However, for findings to be useful, outcomes need to be clinically meaningful, consistently reported across trials, and fully reported. Research has identified the large number of outcomes reported in venous leg ulcer trials, impacting both synthesis of results, and clinical decision-making. To address this, a core outcome set will be developed. A core outcome set is an agreed standardised set of outcomes which should be, as a minimum, measured and reported in all trials which evaluate treatment effectiveness for a given indication. A core outcome set has the potential to reduce research waste, improve the utility of RCTs, reduce reporting bias, facilitate treatment comparisons across different sources of evidence and expedite the production of systematic reviews, meta-analyses and evidence-based clinical guidelines.AimThe aim of this project is to develop a core outcome set for research evaluating the effectiveness of interventions for treating venous leg ulceration.MethodsThrough a scoping review of the literature on venous leg ulceration, we will firstly identify a list of candidate outcome domains (broad categories in relation to what is being measured) from randomised controlled trials and qualitative research, and outcomes (specific methods in relation to what is being measured). In two further stages, we will use the resulting lists of outcome domains and outcomes to design two online surveys. A range of stakeholders will be invited to participate in the surveys and they will be asked to indicate which outcome domains and outcomes are most important and should be considered as core in future research reports.     

Examination of potential novel biochemical factors in relation to prostate cancer incidence and mortality in UK Biobank

Background Although prostate cancer is a leading cause of cancer death, its aetiology is not well understood. We aimed to identify novel biochemical factors for prostate cancer incidence and mortality in UK Biobank.Methods A range of cardiovascular, bone, joint, diabetes, renal and liver-related biomarkers were measured in baseline blood samples collected from up to 211,754 men at recruitment and in a subsample 5 years later. Participants were followed-up via linkage to health administrative datasets to identify prostate cancer cases. Hazard ratios (HRs) and 95% confidence intervals were calculated using multivariable-adjusted Cox regression corrected for regression dilution bias. Multiple testing was accounted for by using a false discovery rate controlling procedure.Results After an average follow-up of 6.9 years, 5763 prostate cancer cases and 331 prostate cancer deaths were ascertained. Prostate cancer incidence was positively associated with circulating vitamin D, urea and phosphate concentrations and inversely associated with glucose, total protein and aspartate aminotransferase. Phosphate and cystatin-C were the only biomarkers positively and inversely, respectively, associated with risk in analyses excluding the first 4 years of follow-up. There was little evidence of associations with prostate cancer death.Conclusion We found novel associations of several biomarkers with prostate cancer incidence. Future research will examine associations by tumour characteristics.Subject terms: Predictive markers, Prostate cancer, Risk factors     

Patterns in metabolite profile are associated with risk of more aggressive prostate cancer: A prospective study of 3,057 matched case–control sets from EPIC

Metabolomics may reveal novel insights into the etiology of prostate cancer, for which few risk factors are established. We investigated the association between patterns in baseline plasma metabolite profile and subsequent prostate cancer risk, using data from 3,057 matched case–control sets from the European Prospective Investigation into Cancer and Nutrition (EPIC). We measured 119 metabolite concentrations in plasma samples, collected on average 9.4 years before diagnosis, by mass spectrometry (AbsoluteIDQ p180 Kit, Biocrates Life Sciences AG). Metabolite patterns were identified using treelet transform, a statistical method for identification of groups of correlated metabolites. Associations of metabolite patterns with prostate cancer risk (OR_1SD) were estimated by conditional logistic regression. Supplementary analyses were conducted for metabolite patterns derived using principal component analysis and for individual metabolites. Men with metabolite profiles characterized by higher concentrations of either phosphatidylcholines or hydroxysphingomyelins (OR_1SD = 0.77, 95% confidence interval 0.66–0.89), acylcarnitines C18:1 and C18:2, glutamate, ornithine and taurine (OR_1SD = 0.72, 0.57–0.90), or lysophosphatidylcholines (OR_1SD = 0.81, 0.69–0.95) had lower risk of advanced stage prostate cancer at diagnosis, with no evidence of heterogeneity by follow-up time. Similar associations were observed for the two former patterns with aggressive disease risk (the more aggressive subset of advanced stage), while the latter pattern was inversely related to risk of prostate cancer death (OR_1SD = 0.77, 0.61–0.96). No associations were observed for prostate cancer overall or less aggressive tumor subtypes. In conclusion, metabolite patterns may be related to lower risk of more aggressive prostate tumors and prostate cancer death, and might be relevant to etiology of advanced stage prostate cancer.     

Evaluating the responsiveness of the endometriosis health profile questionnaire: The EHP-30

OBJECTIVES: To evaluate the sensitivity to change of the Endometriosis Health Profile-30 (EHP-30) questionnaire. SETTING: The Women's Center, John Radcliffe Hospital, Oxford. DESIGN: Postal survey to 66 women undergoing conservative surgery for the treatment of endometriosis-associated pain. The EHP-30 and the Short Form-36 (SF-36) were administered 2 weeks before the operation, and 4 months post-operatively. At T2 a transition question was included to evaluate changes in patients health status. To evaluate responsiveness effect sizes, standardised response means, the index of responsiveness and the minimally and clinically important differences were calculated. RESULTS: Forty (66.6%) patients returned the questionnaires at time 1 and 2. Overall less responsive effect size scores were found for the SF-36 (0.1-0.5) compared to the EHP-30 (-0.1-1.1) for all patients who had undergone treatment. Minimally important differences and the index of responsiveness were overall higher for the EHP-30 (0.4-2.0) compared to the SF-36 (0.1-1.0). Change scores for four of the five scales were significantly correlated with women's responses to the transition question. CONCLUSIONS: Results suggest that the EHP-30 is sensitive to change. Its application in clinical trials should prove beneficial in assessing the impact of medical and surgical interventions upon quality of life for women with endometriosis.     

Computerized follow-up of discrepancies in image interpretation between emergency and radiology departments

Radiographs are ordered and interpreted for immediate clinical decisions 24 hours a day by emergency physicians (EP’s). The Joint Commission for Accreditation of Health Care Organizations requires that all these images be reviewed by radiologists and that there be some mechanism for quality improvement (QI) for discrepant readings. There must be a log of discrepancies and documentation of follow up activities, but this alone does not guarantee effective Q.I. Radiologists reviewing images from the previous day and night often must guess at the preliminary interpretation of the EP and whether follow up action is necessary. EP’s may remain ignorant of the final reading and falsely assume the initial diagnosis and treatment were correct. Some hospitals use a paper system in which the EP writes a preliminary interpretation on the requisition slip, which will be available when the radiologist dictates the final reading. Some hospitals use a classification of discrepancies based on clinical import and urgency, and communicated to the EP on duty at the time of the official reading, but may not communicate discrepancies to the EP’s who initial read the images. Our computerized radiology department and picture archiving and communications system have increased technologist and radiologist productivity, and decreased retakes and lost films. There are fewer face-to-face consultations of radiologists and clinicians, but more communication by telephone and electronic annotation of PACS images. We have integrated the QI process for emergency department (ED) images into the PACS, and gained advantages over the traditional discrepancy log. Requisitions including clinical indications are entered into the Hospital information System and then appear on the PACS along with images and readings. The initial impression, time of review, and the initials of the EP are available to the radiologist dictating the official report. The radiologist decides if there is a discrepancy, and whether it is category I (potentially serious, needs immediate follow-up), category II (moderate risk, follow-up in one day), or category III (low risk, follow-up in several days). During the working day, the radiologist calls immediately for category I discrepancies. Those noted from the evening, night, or weekend before are called to the EP the next morning. All discrepancies with the preliminary interpretation are communicated to the EP and are kept in a computerized log for review by a radiologist at a weekly ED teaching conference. This system has reduced the need for the radiologist to ask or guess what the impression was in the ED the night before. It has reduced the variability in recording of impressions by EP’s, in communication back from radiologists, in the clinical follow-up made, and in the documentation of the whole QI process. This system ensures that EP’s receive notification of their discrepant readings, and provides continuing education to all the EP’s on interpreting images on their patients.     

Single step enrichment of blood dendritic cells by positive immunoselection

Dendritic cells (DC) for cancer immunotherapy protocols are generated most commonly by in vitro differentiation of monocytes with exogenous cytokines (Mo-DC). However, Mo-DC differ in their molecular phenotype and function from blood DC (BDC). Clinical isolation of BDC has been limited to the use of density gradients, which result in low yields of variable purity. We have developed a DC enrichment platform, which uses the CMRF-44 (IgM) or CMRF-56 (IgG) monoclonal antibodies (mAb) to select BDC that express these antigens after a short overnight incubation. After culture of peripheral blood mononuclear cells (PBMC) in autologous/AB serum, biotinylated CMRF-44 was used to select DC in a single step immuno-magnetic bead procedure; this produced populations containing up to 99% CMRF-44(+) cells, including up to 67% CMRF-44(+) CD14(-) CD19(-) DC, from an initial starting population of approximately 0.5%. We observed consistent differences in the purities obtained from individual donors with a mean of 54% CMRF-44(+) cells (range 19-99%). Similar results were obtained using biotinylated CMRF-56 mAb, an antibody identifying a comparable population in cultured PBMC. We recovered an average of 54% and 66% of the available BDC in separations performed with the CMRF-44 and CMRF-56 mAb, respectively. The reproducibility of the procedure and the ability to perform it in a closed sterile system makes it suitable for clinical use. Larger scale preparations starting from apheresis derived PBMC will produce sufficient BDC for immunotherapy protocols. The purified BDC elicited strong allogeneic mixed leukocyte reactions and HLA classes II- and I-restricted antigen-specific primary immune responses.     

Milestones for autonomous in vivo microrobots in medical applications

In light of recent developments within both health care and robotics, the use of robots within the human body has become attainable. Here we discuss the milestones for the realization of autonomous microrobots in medical applications. The desired tasks were classified by identifying the difficulties and requirements faced by the robot. In addition, we classified the levels of autonomy seen in microrobots for these uses. The aim of this article is to provide readers with a good understanding of the current state and future possibilities in this field.